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Combinations of anti-LFA-1, everolimus, anti-CD40 ligand, and allogeneic bone marrow induce central transplantation tolerance through hemopoietic chimerism, including protection from chronic heart allograft rejection.
Metzler, Barbara; Gfeller, Patrick; Bigaud, Marc; Li, Jianping; Wieczorek, Grazyna; Heusser, Christoph; Lake, Philip; Katopodis, Andreas.
Afiliación
  • Metzler B; Autoimmunity and Transplantation, Novartis Institutes for Biomedical Research, Basel, Switzerland. Barbara.Metzler@pharma.novartis.com
J Immunol ; 173(11): 7025-36, 2004 Dec 01.
Article en En | MEDLINE | ID: mdl-15557200
Central transplantation tolerance through hemopoietic chimerism initially requires inhibition of allogeneic stem cell or bone marrow (BM) rejection, as previously achieved in murine models by combinations of T cell costimulation blockade. We have evaluated LFA-1 blockade as part of regimens to support mixed hemopoietic chimerism development upon fully allogeneic BALB/c BM transfer to nonirradiated busulfan-treated B6 recipient mice. Combining anti-LFA-1 with anti-CD40 ligand (CD40L) induced high incidences and levels of stable multilineage hemopoietic chimerism comparable to chimerism achieved with anti-CD40L and everolimus (40-O-(2-hydroxyethyl)-rapamycin) under conditions where neither Ab alone was effective. The combination of anti-LFA-1 with everolimus also resulted in high levels of chimerism, albeit with a lower incidence of stability. Inhibition of acute allograft rejection critically depended on chimerism stability, even if maintained at very low levels around 1%, as was the case for some recipients without busulfan conditioning. Chimerism stability correlated with a significant donor BM-dependent loss of host-derived Vbeta11(+) T cells 3 mo after BM transplantation (Tx). Combinations of anti-CD40L with anti-LFA-1 or everolimus also prevented acute rejection of skin allografts transplanted before established chimerism, albeit not independently of allospecific BMTx. All skin and heart allografts transplanted to stable chimeras 3 and 5 mo after BMTx, respectively, were protected from acute rejection. Moreover, this included prevention of heart allograft vascular intimal thickening ("chronic rejection").
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antígeno-1 Asociado a Función de Linfocito / Trasplante de Médula Ósea / Trasplante de Corazón / Quimera por Trasplante / Anticuerpos Bloqueadores / Ligando de CD40 / Tolerancia al Trasplante / Rechazo de Injerto Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Immunol Año: 2004 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos
Buscar en Google
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antígeno-1 Asociado a Función de Linfocito / Trasplante de Médula Ósea / Trasplante de Corazón / Quimera por Trasplante / Anticuerpos Bloqueadores / Ligando de CD40 / Tolerancia al Trasplante / Rechazo de Injerto Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Immunol Año: 2004 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos